Unlike monogenic diseases whose genetic determinants have been mapped[unreadable] in extended human pedigrees using classical penetrance-based linkage[unreadable] analysis methods, many common diseases involve multiple genetic and[unreadable] environmental components and their interactions. The genetic analysis[unreadable] of such complex phenotypes requires new statistical approaches for the[unreadable] localization and evaluation of the relative importance of specific[unreadable] quantitative trait loci (QTLs). In this application, the investigators[unreadable] propose to develop/extend a number of new statistical genetic analytical[unreadable] methods for the localization and evaluation of QTLs influencing common[unreadable] human diseases. To address this critical area of genetic research, they[unreadable] have formed a new collaborative scientific team combining two major[unreadable] statistical genetic working groups based at the Southwest Foundation for[unreadable] Medical Research (led by Dr. Blangero) and the University of California[unreadable] at Los Angeles (led by Dr. Lange). Unlike most work in this nascent[unreadable] field, they will concentrate their efforts on methods for the analysis[unreadable] of common diseases and other complex phenotypes in extended human[unreadable] pedigrees. In particular, they will focus largely on extensions of the[unreadable] variance component method of linkage analysis. They will also further[unreadable] develop and extend their linkage analysis software (SOLAR) so that it[unreadable] becomes a comprehensive, yet easily used, package for the oligogenic[unreadable] analysis of quantitative human variation.[unreadable] [unreadable] The proposed research will address five specific aims: 1) The[unreadable] investigators will develop and extend the variance component linkage[unreadable] procedures to allow for general multivariate analysis, oligogenic[unreadable] inheritance, epistasis, genotype x environment interaction, and[unreadable] empirical genome-wide p-value evaluations; 2) They will develop more[unreadable] efficient methods for the calculation of IBD probability matrices in[unreadable] complex pedigrees; 3) A general variance component method for the[unreadable] linkage analysis of discrete traits and the joint analysis of discrete[unreadable] and quantitative traits will be formulated, tested, and implemented in[unreadable] the SOLAR package; 4) Two new methods for fine mapping QTLs in extended[unreadable] pedigrees will be developed and evaluated including joint[unreadable] disequilibrium/linkage analysis using variance component model and a[unreadable] novel gamete competition model; and 5) All of the above methods will be[unreadable] incorporated into the software package (SOLAR) for linkage analysis of[unreadable] complex traits in extended pedigrees.